1. Analysis of the BRCA1 and BRCA2 genes in Breast and Prostate Cancer. Breast cancer remains the most common malignancy in females in the United States and is a major public health problem. Although progress has been made in prevention, early detection, and therapy, 37,500 women die of this malignancy annually. Analysis of breast cancer families resulted in the identification of two major loci, BRCA1 and BRCA2. We designed a clinical study to address some of these issues, with recruitment of Hispanic women with breast cancer through community organizations, clinics with large Hispanic populations, public events, and the internet. (http://clinicaltrials.gov/show/NCT01251900). We recruited a total of 200 Hispanic breast cancer subjects from 10 different states, and had an 88% success rate in completion of collection of consent, questionnaire, saliva sample, and pathology report. The use of a saliva collection device that can be sent by regular mail allowed the materials cost of collection, shipping, and DNA extraction to be under $25. A total of seven clearly deleterious alleles were identified, including a newly described allele, a single nucleotide deletion in BRCA1 (6005delT). The other six alleles were unique and, except for E1308X in BRCA2, all represent mutations uncommonly seen in these genes. Six of the seven mutations are frameshift or termination codons. The one missense variant is a compound allele C1787S and G1788D. These alleles have been reported 5 times in the Breast Information Core (BIC) (http://research.nhgri.nih.gov/projects/bic) and have been proposed to be in cis, on the same allele; next-generation sequencing confirmed this. The same approach was used to sequence 300 unselected breast cancer patients from two centers in Puerto Rico. Table 2 displays the variants identified. Interestingly, Puerto Rican breast cancer has predominately BRCA2 mutations and a high frequency of the E1308X mutation. BRCA1 and BRCA2 mutation carriers have a higher risk of prostate cancer as well as recurrent and lethal disease. Therefore we sequenced 800 prostate cancer patients from Walter Reed Hospital. Variants in both genes were identified with a somewhat higher rate of BRCA2 alleles compared to BRCA1 2. Bladder Cancer: Whole Exome Sequencing and Application Bladder cancer is one of the most common tumors in the US and is the most expensive to treat. To understand the molecular basis of this malignancy we subjected 99 Chinese and 14 US primary urothelial bladder tumors to exome sequencing. Validated somatic variants in US tumors were observed in 67 genes including 10 indels, 22 nonsense, 78 missense, and 2 variants in splice junctions. Twenty genes were mutated in 1 tumor, including genes known to be mutated in bladder cancer such as FGFR3, TP53, and TSC1. Eight genes were altered in 3 or more tumors and are referred to as frequently mutated genes (FMG), including previously identified genes, KDM6A and ARID1A, altered in four and three tumors, respectively. Four altered genes are novel bladder cancer FMGs when compared to other studies: BRCA1 associated protein-1 (BAP1), chromodomain helicase DNA binding protein 1 (CHD1), chromodomain helicase DNA binding protein 1-like (CHD1L), and GCN1 general control of amino-acid synthesis 1-like 1 (GCN1L1). These genes are of particular interest as they encode proteins that have distinct roles in chromatin remodeling (CRM) 3. Pediatric cancer in Latin America-Epidemiology and Genetic Analysis We now have over 1250 patient samples representing 80% of the current patients and survivors from the Unidad Nacional de Oncologia Pediatrica (UNOP), in Guatemala. A similar effort was started in 2014 at the Hospital La Mascota in Nicaragua where both cancer and cases of pediatric genetic disease are being recruited. These combined studies represent one of the most extensive for pediatric oncology in Latin America. Retinoblastoma is one of the most common pediatric solid tumors in Mexicoand Central America, accounting for up to 10% of all diagnosed cases. To further understand the factors involved in the higher prevalence, we performed an analysis of 327 consecutive cases treated over 10 years at UNOP the sole pediatric cancer hospital in Guatemala. From this data we calculated the incidence of retinoblastoma to be 8.1 cases/million children under the age of 14 in the Guatemala City region. This incidence is elevated two-fold over the incidence in the United States and Europe, and is similar in indigenous and admixed populations in the capital region. The elevated incidence is not due to an increase in familial cases, suggesting an environmental contributor. Analysis of retinoblastoma incidence in indigenous and admixed populations demonstrates a lower ascertainment in indigenous children and in rural areas farther from the capitol. This disparity is even more pronounced in acute lymphocytic leukemia. To support our hypothesis that the lower observed incidence of rural indigenous retinoblastoma cases is due to late or absent diagnosis, we compared the mortality and stage of diagnosis of indigenous and non-indigenous admixed cases. We found a significantly higher mortality of indigenous cases (65 vs. 40%, P= 0.00011). Survival analysis from diagnosis demonstrated a highly significant difference [Hazard Ratio 2.66 (1.86-3.82) P = 2.45x10-8] for indigenous cases. 4. Cervical cancer genomics. Cervical cancer is the most frequently fatal malignancy in women living in poverty with over 85% of deaths occurring in the poorest women of the world. Over 30,000 women die of cervical cancer in the Americas. To determine the lifestyle factors, HPV strains and molecular characteristics of Latin American women with cervical tumors, subjects were prospectively enrolled and tumor tissue and blood collected at the Instituto de Cancerologia (Guatemala) and the Hospital Central Universitario (Venezuela). The 293 patients with cervical cancer (CC) from Guatemala have an average age of 50 years and 33 subjects from Venezuela with CC an average age of 47. The Guatemalan patients have significantly more pregnancies (6.1 vs 4.4) and are less likely to use oral contraceptives or tobacco products, but are 10 times more likely to cook in the home with wood. To identify potential cancer genes, 23 Guatemalan CC and corresponding normal DNAs were subjected to exome capture and sequencing. Variants in genes predicted to be mutated in two or more tumors, in known somatic cancer genes or in genes previously shown to be mutated in cervical cancer. Predicted somatic mutations were found in known cancer genes including PIK3CA, RB1, TP53, MAPK1, HRAS, KRAS, TSC1, BRCA1, BRCA2, BAP1, and ATM. The same tumor and normal DNAs were also amplified for all exons, using the AmpliSeq Exome protocol, and copy number determination performed. As seen previously in cervical cancer, nearly all Guatemalan tumors have 3-5 copies of chromosome 3q, and 14/23 have chromosome loss at 17p containing the TP53 locus. In total 9/23 cervical tumors show evidence of extensive chromosomal rearrangement or chromothripsis.